Acromegaly Disease Control Maintained After Switching From Injected Somatostatin Receptor Ligands to Oral Paltusotine.

CONTEXT: Paltusotine is a nonpeptide selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly. OBJECTIVE: To evaluate the efficacy and safety of paltusotine in the treatment of patients with acromegaly previously controlled with injected somatostatin receptor ligands (SRLs). METHODS: This phase 3, randomized, double-blind, placebo-controlled trial enrolled adults with acromegaly who had insulin-like growth factor I (IGF-I) ≤1.0 times the upper limit of normal (×ULN) while receiving a stable dose of depot octreotide or lanreotide. Patients were switched from injected SRLs and randomized to receive paltusotine or placebo orally for 36 weeks. The primary endpoint was proportion of patients maintaining IGF-I ≤1.0×ULN. Secondary endpoints were change in IGF-I level, change in Acromegaly Symptom Diary (ASD) score, and maintenance of mean 5-sample growth hormone (GH) <1.0 ng/mL. RESULTS: The primary endpoint was met: 83.3% (25/30) of patients receiving paltusotine and 3.6% (1/28) receiving placebo maintained IGF-I ≤1.0×ULN (odds ratio: 126.53; 95% CI: 13.73, >999.99; P<.0001). Paltusotine was also superior to placebo for all secondary endpoints: mean (±SE) change in IGF-I of 0.04±0.09×ULN versus 0.83±0.1×ULN (P<.0001); mean (±SE) change in ASD score of -0.6±1.5 versus 4.6±1.6 (P=.02); mean GH maintained at <1.0 ng/mL in 20/23 (87.0%) versus 5/18 (27.8%) patients (odds ratio: 16.61; 95% CI: 2.86, 181.36; P=.0003). The most common adverse events were acromegaly symptoms and gastrointestinal effects characteristic of SRLs. CONCLUSION: Replacement of injected SRLs by once-daily oral paltusotine was effective in maintaining both biochemical and symptom control in patients with acromegaly and was well tolerated.

Fracture Risk Assessment and Drug Holiday in a Real-Life Setting.

PURPOSE: Describe fracture risk assessment practices among physicians treating osteoporosis in a real-life setting. METHODS: This is a retrospective cohort study in a tertiary academic center. Inclusion criteria involved adults (aged ≥18 years) who received minimum adequate therapy (bisphosphates, raloxifene, or denosumab ≥ 3 years or teriparatide ≥ 18 months). Of 1,814 charts randomly selected and reviewed, 274 patients met the inclusion criteria. Risk stratification tools included fragility fractures, Dual-energy X-ray Absorptiometry (DXA), and fracture risk assessment using the FRAX tool. Fracture risk assessment was performed before therapy initiation (N= 274) and at the time of institution of the drug holiday (N=119). High-risk patients were defined as the presence of a fragility fracture, T-score ≤-2.5, or a high-risk score by FRAX calculation. FRAX scores were independently calculated by the research team for comparison and assessment purposes. RESULTS: Before initiation of therapy (N=274) versus upon starting a drug holiday (DH; N=119), 29.9% versus 3.4% had a history of fragility fractures (P<0.001), 58.8% versus 67.2% had a DXA scan performed (P>0.05), 10.5% versus 10.9% of physicians calculated a FRAX score (P>0.05), and 71.5% versus 66.4% were considered at high risk and eligible for therapy. A DXA scan was performed after DH in 40.2% of these patients and at least once in 95.3% of the entire cohort. CONCLUSION: The reporting of FRAX score in DXA scan reports may significantly increase its utilization in fracture risk assessment. We recommend comprehensive fracture risk assessment utilizing history of prevalent osteoporosis fractures, DXA assessment, and FRAX scoring.

Patterns of Osteoporosis Medications Selection After Drug Holiday or Continued Therapy: A Real-World Experience.

OBJECTIVE: Published literature on physicians' preferences and sequential treatment patterns of osteoporosis therapy is scarce. METHODS: A retrospective cohort study of patients who received bisphosphonates, denosumab, and/or raloxifene for at least 3 consecutive years or teriparatide for at least 18 months for osteoporosis. Data collection spanned 10 years, from October 2007 to September 2016, at a tertiary care center in the United States. RESULTS: In total, 12 885 patients were identified on the basis of receiving at least 1 treatment at any point in time; 1814 patients were randomly reviewed, and 274 patients met the inclusion criteria. The mean age was 68.8 ± 10.7 years, and women represented 90.9% of all the cases. Primary care physicians and rheumatologists constituted 65.7% and 22.6% of the prescribers, respectively. Before instituting a drug holiday, alendronate was the most common initial treatment (percentage, mean duration ± standard deviation in years: 69%, 5.4 ± 2.4 years) followed by ibandronate (9.5%, 4.9 ± 2.1 years) and raloxifene (9.1%, 5.2 ± 1.6 years). Denosumab was the most common second course of treatment, accounting for 29.3% of 82 patients who were subsequently prescribed another therapy, followed by alendronate (24.4%) and zoledronate (20.7%). Among patients who were placed on a drug holiday and eventually restarted on osteoporosis therapy, denosumab was the most common treatment instituted (n = 21), accounting for 40% of the total patients, followed by alendronate (32%) and zoledronate (16%). There was a progressive decline in osteoporosis therapy over the duration of the study. CONCLUSION: Alendronate was the most common initial therapy. Denosumab was the most common second course of treatment prescribed.

Oxytocin alterations and neurocognitive domains in patients with hypopituitarism.

PURPOSE: Oxytocin is a hypothalamus derived, posterior pituitary stored nonapeptide which has gained recent interest as an important neuropsychiatric and metabolic hormone beyond its classic role in lactation and parturition. Hypopituitarism is a heterogenous disorder of derangement in one or more anterior or posterior pituitary hormones. Diagnosis of deficiency and hormone replacement exists to address all relevant axes except for oxytocin. Our study aims to define derangements in oxytocin in a unique population of patients with hypopituitarism and correlate levels with measures of emotional health and quality of life. METHODS: A cross-sectional, single day study was completed to measure plasma oxytocin levels in a diverse population of patients with hypopituitarism compared to controls. Subjects also completed depression, quality of life and stress-related questionnaires, and emotion recognition tasks. RESULTS: Thirty-eight subjects completed the study, 18 with hypopituitarism (9 with diabetes insipidus) and 20 controls. After controlling for differences in age, weight and gender, plasma oxytocin levels were highest in subjects with diabetes insipidus compared to control [mean, IQR: 44.3 pg/ml (29.8-78.2) vs. 20.6 (17-31.3), p = 0.032]. Amongst hypopituitary subjects, those with duration of disease greater than 1 year had higher oxytocin levels. No significant differences were observed for psychosocial measures including emotion recognition tasks. CONCLUSIONS: Plasma oxytocin levels were found higher in patients with hypopituitarism compared to controls and highest in those with diabetes insipidus. Longer duration of hypopituitarism was also associated with higher plasma levels of oxytocin. Further study is needed to better define oxytocin deficiency and investigate response to treatment.

Long-Term Remission of Acromegaly after Octreotide Withdrawal Is an Uncommon and Frequently Unsustainable Event.

BACKGROUND: Long-term remission of acromegaly after somatostatin analog withdrawal has been reported in 18-42% of patients in studies with a relatively small number of patients using different inclusion and remission criteria. The objectives of this study were to establish the probability and predictive factors for short- and long-term remission [normal IGF-1 for age/sex: IGF-1 ≤1.00 × upper limit of normal (ULN)] after octreotide long-acting release (LAR) withdrawal in a larger population of well-controlled patients with acromegaly (normal mean IGF-1 in the last 24 months). METHODS: This is a prospective multicenter study in which 58 well-controlled patients with acromegaly receiving only octreotide LAR as a primary or postsurgical treatment were included in 14 university centers in Brazil. All patients had been on stable doses and dose intervals of octreotide LAR in the last year, and none had been submitted to radiotherapy. The main outcome measure was serum IGF-1 after 8 weeks (short-term) and 60 weeks (long-term) of octreotide LAR withdrawal. RESULTS: Seventeen of 58 patients (29%) were in remission in the short term, and only 4 patients achieved long-term remission after treatment withdrawal. The Kaplan-Meier estimated remission probability at 60 weeks was 7% and decreased to 5% at 72 weeks. The short-term remission rate was significantly higher (44%; p = 0.017) in patients with pretreatment IGF-1 <2.4 × ULN. No other predictive factor for short- or long-term remission was found. CONCLUSION: Our results show that long-term remission of acromegaly after octreotide LAR withdrawal was an uncommon and frequently unsustainable event and do not support the recommendation of a systematic withdrawal of treatment in controlled patients.

Effects of oral and transdermal estrogen on IGF1, IGFBP3, IGFBP1, serum lipids, and glucose in patients with hypopituitarism during GH treatment: a randomized study.

OBJECTIVE: To evaluate the effects of oral estradiol and transdermal 17ß-estradiol on serum concentrations of IGF1 and its binding proteins in women with hypopituitarism. DESIGN: Prospective, comparative study. METHODS: Eleven patients with hypopituitarism were randomly allocated to receive 2 mg oral estradiol (n=6) or 50 µg/day of transdermal 17ß-estradiol (n=5) for 3 months. RESULTS: The oral estrogen group showed a significant reduction in IGF1 levels (mean: 42.7%±41.4, P=0.046); no difference was observed in the transdermal estrogen group. There was a significant increase in IGFBP1 levels (mean: 170.2%±230.9, P=0.028) in the oral group, but not in the transdermal group. There was no significant difference within either group in terms of median IGFBP3 levels. In relation to lipid profiles, there was a significant increase in mean high-density lipoprotein cholesterol levels in the oral group after 3 months of treatment, (27.8±9.3, P=0.003). We found no differences in the anthropometric measurements, blood pressure, heart rate, glucose, insulin, C-peptide, or the homeostasis model assessment index after treatment. CONCLUSIONS: Our preliminary data indicate that different estrogen administration routes can influence IGF1 and IGFBP1 levels. These findings in patients with hypopituitarism have an impact on their response to treatment with GH, since patients receiving oral estrogen require increased GH dosage. These results suggest that oral estrogens may reduce the beneficial effects of GH replacement on fat and protein metabolism, body composition, and quality of life.

Criteria of cure and remission in Cushing's disease: an update: [review]

We review the clinical and biochemical criteria used for evaluation of the transsphenoidal pituitary surgery results in the treatment of Cushing's disease (CD). Firstly, we discuss the pathophysiology of the hypothalamic-pituitary-adrenal axis in normal subjects and patients with CD. Considering the series published in the last 25 years, we observed a significant variation in the remission or cure criteria, including the choice of biochemical tests, timing, threshold values to define remission, and the interference of glucocorticoid replacement or previous treatment. In this context we emphasize serum cortisol levels obtained early (from hours to 12 days) in the postoperative period without any glucocorticoid replacement or treatment. Our experience demonstrates that: (i) early cortisol < 5 to 7 µg/dl, (ii) a period of glucocorticoid dependence > 6 mo, (iii) absence of response of cortisol/ACTH to CRH or DDAVP, (iv) return of dexamethasone suppression, and circadian rhythm of cortisol are appropriate indices of remission of CD. In patients with undetectable cortisol levels early after surgery, recurrence seems to be low. Finally, although certain biochemical patterns are more suggestive of remission or surgical failure, none has been proven to be completely accurate, with recurrence observed in approximately 10 to 15 percent of the patients in long-term follow-up. We recommended that patients with CD should have long-term monitoring of the CRH-ACTH-cortisol axis and associated co-morbidities, especially hypopituitarism, diabetes mellitus, hypertension, cardiovascular disturbances, and osteoporosis.

Neste artigo, são revisados os principais critérios clínicos e hormonais utilizados para avaliação do tratamento cirúrgico da Doença de Cushing (DC). Inicialmente são comentados aspectos fisiopatológicos que orientam a avaliação hormonal e os principais fatores clínicos, laboratoriais, cirúrgicos e histológicos associados com melhores resultados, observados nas principais séries da literatura e em pacientes acompanhados prospectivamente pelos autores. Foram revisados, também, critérios adotados nas principais séries da literatura, nos últimos 25 anos, chamando-se atenção para as dosagens hormonais, o momento em que foram realizadas, a possibilidade de interferência de tratamentos prévios e da reposição glicocorticóide. À seguir, essas dosagens são discutidas salientando-se a importância do cortisol obtido seqüencialmente no pós-operatório e sem a interferência de reposição glicocorticóide. A experiência prospectiva dos autores, recentemente referendada na literatura, demonstra que valores de cortisol < 5 a 7 µg/dl associados com um período de dependência aos glicocorticóides > 6 meses, ausência de resposta do ACTH/cortisol ao DDAVP e/ou CRH, retorno da supressão à dexametasona e do ritmo circadiano, estão associados com remissão da DC. Em pacientes com cortisol indetectável após cirurgia transesfenoidal, a chance de recidiva parece ser menor do que naqueles em que se observa cortisol detectável. Finalmente, chamamos a atenção para que, mesmo adotando critérios rígidos de avaliação, a recidiva da DC pode ocorrer a longo prazo em até 15 por cento dos casos, recomendando-se, portanto, que esses pacientes sejam acompanhados por tempo indeterminado, com monitorização cuidadosa do eixo CRH-ACTH-cortisol e de suas co-morbidades, especialmente hipopituitarismo, diabete melito, hipertensão arterial, alterações cardiovasculares e osteoporose.

[Growth hormone (GH) and IGF-I assays: methodological aspects and its implications in acromegaly diagnosis and follow-up]. / Ensaios para a medida de hormônio do crescimento (GH) e IGF-I: aspectos metodológicos e suas implicações no diagnóstico e seguimento da acromegalia.

Growth hormone quantification in serum is essential for confirming or ruling out its excess. The absence of clinical criteria sufficiently sensitive to evaluate the treatment success enables GH as the key diagnostic procedure and for that, its measurements must be done in a reliable way and must allow uniform interpretation. Several different biochemical criteria for remission have been suggested in the past, including a random GH measurement less than 2.5 microg/l, mean GH value from a day curve less than 2.5 microg/l, nadir GH value after an oral glucose tolerance test (OGGT) less than 1.0 microg/l and a normal age-related IGF-I level. The importance of adequate treatment is highlighted by data indicating that lowering GH levels to less than 2.5 microg/l reverses the premature mortality of acromegaly. With the advances of ultrasensitive assays for GH measurement, strictest remission criteria to determine remission or cure were necessary. In this review, we describe the changes of assay methodology and its consequences in serum GH results and cut off point values to define activity and remission of acromegaly.

Ensaios para a medida de hormônio do crescimento (GH) e IGF-I: aspectos metodológicos e suas implicações no diagnóstico e seguimento da acromegalia / Growth hormone (GH) and IGF-I assays: methodological aspects and its implications in acromegaly diagnosis and follow-up

A dosagem do GH no soro é essencial para confirmar ou excluir o seu excesso. Na acromegalia, a ausência de critérios clínicos suficientemente sensíveis para monitorizar o sucesso do tratamento faz com que o GH sérico seja o procedimento de escolha e, para isso, é essencial que a sua dosagem seja realizada de forma confiável, capaz de permitir interpretações uniformes. Vários critérios hormonais têm sido propostos para caracterizar remissão da acromegalia, incluindo níveis séricos de GH randômico inferior a 2,5 µg/l, nadir de GH durante o teste de tolerância oral a glicose inferior a 1,0 µg/l e IGF-I normal para sexo e idade. A importância do tratamento adequado consiste na possibilidade de reverter a mortalidade prematura da acromegalia através da diminuição dos níveis de GH para valores menores que 2,5 µg/l. Com o surgimento de ensaios ultra-sensíveis para medida do GH, tornaram-se necessários critérios mais estritos para determinar cura ou remissão da doença. Nesta revisão, descreveremos aqui as modificações decorrentes da evolução dos ensaios, as conseqüências nos resultados de GH e os pontos de corte propostos na literatura para caracterização da atividade e remissão da acromegalia.

Growth hormone quantification in serum is essential for confirming or ruling out its excess. The absence of clinical criteria sufficiently sensitive to evaluate the treatment success enables GH as the key diagnostic procedure and for that, its measurements must be done in a reliable way and must allow uniform interpretation. Several different biochemical criteria for remission have been suggested in the past, including a random GH measurement less than 2.5 µg/l, mean GH value from a day curve less than 2.5 µg/l, nadir GH value after an oral glucose tolerance test (OGGT) less than 1.0 µg/l and a normal age-related IGF-I level. The importance of adequate treatment is highlighted by data indicating that lowering GH levels to less than 2.5 µg/l reverses the premature mortality of acromegaly. With the advances of ultrasensitive assays for GH measurement, strictest remission criteria to determine remission or cure were necessary. In this review, we describe the changes of assay methodology and its consequences in serum GH results and cut off point values to define activity and remission of acromegaly.

Criteria of cure and remission in Cushing's disease: an update.

We review the clinical and biochemical criteria used for evaluation of the transsphenoidal pituitary surgery results in the treatment of Cushing's disease (CD). Firstly, we discuss the pathophysiology of the hypothalamic-pituitary-adrenal axis in normal subjects and patients with CD. Considering the series published in the last 25 years, we observed a significant variation in the remission or cure criteria, including the choice of biochemical tests, timing, threshold values to define remission, and the interference of glucocorticoid replacement or previous treatment. In this context we emphasize serum cortisol levels obtained early (from hours to 12 days) in the postoperative period without any glucocorticoid replacement or treatment. Our experience demonstrates that: (i) early cortisol < 5 to 7 microg/dl, (ii) a period of glucocorticoid dependence > 6 mo, (iii) absence of response of cortisol/ACTH to CRH or DDAVP, (iv) return of dexamethasone suppression, and circadian rhythm of cortisol are appropriate indices of remission of CD. In patients with undetectable cortisol levels early after surgery, recurrence seems to be low. Finally, although certain biochemical patterns are more suggestive of remission or surgical failure, none has been proven to be completely accurate, with recurrence observed in approximately 10 to 15% of the patients in long-term follow-up. We recommended that patients with CD should have long-term monitoring of the CRH-ACTH-cortisol axis and associated co-morbidities, especially hypopituitarism, diabetes mellitus, hypertension, cardiovascular disturbances, and osteoporosis.

Tumores não hipofisários da região selar / Nonpituitary tumors of the sellar region

A hipófise, a sela túrcica e a região peri-selar podem ser acometidas por uma série de lesões, incluindo tumores benignos e malignos, bem como uma ampla variedade de doenças não neoplásicas. Os aspectos clínicos e radiológicos podem auxiliar no diagnóstico diferencial destas lesões. Porém, em muitos casos, somente a análise histopatológica pode estabelecer o diagnóstico definitivo. Neste artigo, revisamos principais tumores não hipofisários da região selar e peri-selar, ressaltando seus aspectos endócrinos mais relevantes.

[Nonpituitary tumors of the sellar region]. / Tumores não hipofisários da região selar.

The pituitary gland, sella turcica and the parasellar region can be involved by a wide variety of lesions, including benign and malignant neoplasms as well as a wide variety of non neoplastic tumor-like lesions. Clinical and radiological aspects could help in the differential diagnosis of these lesions. Nevertheless, in many cases only the histopathological analysis could establish the definitive diagnosis. In this paper, we review the nonpituitary tumors of the sellar region emphasizing the associated hormonal disturbances.